scholarly journals Comparison of the Physicochemical, Antifungal, and Toxic Properties of Two Liposomal Amphotericin B Products

2007 ◽  
Vol 52 (1) ◽  
pp. 259-268 ◽  
Author(s):  
Jon A. Olson ◽  
Jill P. Adler-Moore ◽  
Gerard M. Jensen ◽  
Julie Schwartz ◽  
M. Cecilia Dignani ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Liposomal Amphotericin ◽  
Lethal Dose ◽  
Drug Efficacy ◽  
Liposomal Amphotericin B ◽  
In Vitro Tests ◽  
Tubular Necrosis ◽  
Weight Loss Data ◽  
Renal Tubular

ABSTRACT Small unilamellar amphotericin B liposomes can reduce the toxicity of amphotericin B. In this study, we compared the physical, antifungal, pharmocokinetic, and toxic properties of two liposomal amphotericin B products, AmBisome and Anfogen, that have the same chemical composition but are manufactured differently. In vitro tests included determinations of the MICs and the concentrations causing the release of 50% of the intracellular potassium from red blood cells (K50 values) to assess toxicity. The 50% lethal dose (LD50) was evaluated by using uninfected C57BL/6 mice and single intravenous (i.v.) doses of 1 to 100 mg/kg of body weight. Multiple i.v. dosing over 18 days was performed with 0.5, 1.0, or 5.0 mg of Anfogen/kg or 1.0, 5.0, or 25 mg of AmBisome/kg to evaluate chronic toxicity. DBA/2 mice were infected intranasally with 2.5 × 106 Aspergillus fumigatus conidia, treated for 3 or 4 days with 3.0, 5.0, or 7.5 mg of Anfogen/kg or 3, 5, 7.5, or 15 mg of AmBisome/kg, and evaluated to assess the toxicity of the drugs to the kidneys (by measurement of blood urea nitrogen and creatinine levels and histopathology) and the drug efficacy. The median particle size was 77.8 nm for AmBisome and 111.5 nm for Anfogen. In vitro K50 values were significantly lower for Anfogen (0.9 μg/ml) than for AmBisome (20 μg/ml), and the LD50 of AmBisome was >100 mg/kg, versus 10 mg of Anfogen/kg. There was significant renal tubular necrosis in uninfected and infected mice given Anfogen but no tubular necrosis in AmBisome-treated mice. AmBisome at 7.5 or 15 mg/kg was also more efficacious than 7.5 mg of Anfogen/kg for the treatment of pulmonary aspergillosis, based on survival and weight loss data and numbers of CFU per gram of lung. In conclusion, the efficacy and toxicity of these two liposomal amphotericin B products were significantly different, and thus, the products were not comparable.

scholarly journals Assessment of Efficacy of Antifungals against Aspergillus fumigatus: Value of Real-Time Bioluminescence Imaging

2013 ◽  
Vol 57 (7) ◽  
pp. 3046-3059 ◽  
Author(s):  
Célimène Galiger ◽  
Matthias Brock ◽  
Grégory Jouvion ◽  
Amélie Savers ◽  
Marianna Parlato ◽  
...  
Keyword(s):  
Aspergillus Fumigatus ◽  
Real Time ◽  
Amphotericin B ◽  
Liposomal Amphotericin ◽  
Bioluminescence Imaging ◽  
Treatment Success ◽  
Drug Efficacy ◽  
Liposomal Amphotericin B

ABSTRACTAspergillus fumigatuscauses life-threatening infections, especially in immunocompromised patients. Common drugs for therapy of aspergillosis are polyenes, azoles, and echinocandins. However, despitein vitroefficacy of these antifungals, treatment failure is frequently observed. In this study, we established bioluminescence imaging to monitor drug efficacy underin vitroandin vivoconditions.In vitroassays confirmed the effectiveness of liposomal amphotericin B, voriconazole, and anidulafungin. Liposomal amphotericin B and voriconazole were fungicidal, whereas anidulafungin allowed initial germination of conidia that stopped elongation but allowed the conidia to remain viable.In vivostudies were performed with a leukopenic murine model. Mice were challenged by intranasal instillation with a bioluminescent reporter strain (5 × 105and 2.5 × 105conidia), and therapy efficacies of liposomal amphotericin B, voriconazole, and anidulafungin were monitored. For monotherapy, the highest treatment efficacy was observed with liposomal amphotericin B, whereas the efficacies of voriconazole and anidulafungin were strongly dependent on the infectious dose. When therapy efficacy was studied with different drug combinations, all combinations improved the rate of treatment success compared to that with monotherapy. One hundred percent survival was obtained for treatment with a combination of liposomal amphotericin B and anidulafungin, which prevented not only pulmonary infections but also infections of the sinus. In conclusion, combination therapy increases treatment success, at least in the murine infection model. In addition, our novel approach based on real-time imaging enablesin vivomonitoring of drug efficacy in different organs during therapy of invasive aspergillosis.

Differential effects of amphotericin B and liposomal amphotericin B on inflammatory cells in vitro

2002 ◽  
Vol 51 (5) ◽  
pp. 259-264 ◽  
Author(s):  
R. Baronti ◽  
E. Masini ◽  
L. Bacciottini ◽  
P. F. Mannaioni
Keyword(s):  
Amphotericin B ◽  
Liposomal Amphotericin ◽  
Inflammatory Cells ◽  
Liposomal Amphotericin B ◽  
Differential Effects

scholarly journals Plasma Protein Binding of Amphotericin B and Pharmacokinetics of Bound versus Unbound Amphotericin B after Administration of Intravenous Liposomal Amphotericin B (AmBisome) and Amphotericin B Deoxycholate

2002 ◽  
Vol 46 (3) ◽  
pp. 834-840 ◽  
Author(s):  
Ihor Bekersky ◽  
Robert M. Fielding ◽  
Dawna E. Dressler ◽  
Jean W. Lee ◽  
Donald N. Buell ◽  
...  
Keyword(s):  
Human Plasma ◽  
Amphotericin B ◽  
Liposomal Amphotericin ◽  
The Body ◽  
Liposomal Amphotericin B ◽  
Time Curve ◽  
Liposomal Drug ◽  
Drug Concentrations ◽  
Unique Composition

ABSTRACT Unilamellar liposomal amphotericin B (AmBisome) (liposomal AMB) reduces the toxicity of this antifungal drug. The unique composition of liposomal AMB stabilizes the liposomes, producing higher sustained drug levels in plasma and reducing renal and hepatic excretion. When liposomes release their drug payload, unbound, protein-bound, and liposomal drug pools may exist simultaneously in the body. To determine the amounts of drug in these pools, we developed a procedure to measure unbound AMB in human plasma by ultrafiltration and then used it to characterize AMB binding in vitro and to assess the pharmacokinetics of nonliposomal pools of AMB in a phase IV study of liposomal AMB and AMB deoxycholate in healthy subjects. We confirmed that AMB is highly bound (>95%) in human plasma and showed that both human serum albumin and α1-acid glycoprotein contribute to this binding. AMB binding exhibited an unusual concentration dependence in plasma: the percentage of bound drug increased as the AMB concentration increased. This was attributed to the low solubility of AMB in plasma, which limits the unbound drug concentration to <1 μg/ml. Subjects given 2 mg of liposomal AMB/kg of body weight had lower exposures (as measured by the maximum concentration of drug in serum and the area under the concentration-time curve) to both unbound and nonliposomal drug than those receiving 0.6 mg of AMB deoxycholate/kg. Most of the AMB in plasma remained liposome associated (97% at 4 h, 55% at 168 h) after liposomal AMB administration, so that unbound drug concentrations remained at <25 ng/ml in all liposomal AMB-treated subjects. Although liposomal AMB markedly reduces the total urinary and fecal recoveries of AMB, urinary and fecal clearances based on unbound AMB were similar (94 to 121 ml h−1 kg−1) for both formulations. Unbound drug urinary clearances were equal to the glomerular filtration rate, and tubular transit rates were <16% of the urinary excretion rate, suggesting that net filtration of unbound drug, with little secretion or reabsorption, is the mechanism of renal clearance for both conventional and liposomal AMB in humans. Unbound drug fecal clearances were also similar for the two formulations. Thus, liposomal AMB increases total AMB concentrations while decreasing unbound AMB concentrations in plasma as a result of sequestration of the drug in long-circulating liposomes.

Aerosolized liposomal amphotericin B: Prediction of lung deposition, in vitro uptake and cytotoxicity

2012 ◽  
Vol 436 (1-2) ◽  
pp. 106-110 ◽  
Author(s):  
Mélanie Fauvel ◽  
Cécile Farrugia ◽  
Nicolas Tsapis ◽  
Claire Gueutin ◽  
Odile Cabaret ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Liposomal Amphotericin ◽  
Lung Deposition ◽  
Liposomal Amphotericin B ◽  
In Vitro Uptake

scholarly journals Investigation of the Efficacy of Micafungin in the Treatment of Histoplasmosis Using Two North American Strains of Histoplasma capsulatum

2011 ◽  
Vol 55 (9) ◽  
pp. 4447-4450 ◽  
Author(s):  
Chadi A. Hage ◽  
Patricia Connolly ◽  
Daniel Horan ◽  
Michelle Durkin ◽  
Melinda Smedema ◽  
...  
Keyword(s):  
Amphotericin B ◽  
North American ◽  
Liposomal Amphotericin ◽  
Histoplasma Capsulatum ◽  
Liposomal Amphotericin B ◽  
Content Type ◽  
Yeast Form

ABSTRACTMicafungin alone and combined with liposomal amphotericin B was evaluated against two strains ofHistoplasma capsulatum. Micafungin was activein vitroagainst the mold but not the yeast form but was ineffectivein vivo. Micafungin appears to be ineffective in treatment of histoplasmosis.

Comparison of antifungal efficacies of moxifloxacin, liposomal amphotericin B, and combination treatment in experimental Candida albicans endophthalmitis in rabbits

2010 ◽  
Vol 56 (1) ◽  
pp. 1-7 ◽  
Author(s):  
Yudum Tiftikcioğlu Deren ◽  
Şengül Özdek ◽  
Ayşe Kalkanci ◽  
Nalan Akyürek ◽  
Berati Hasanreisoğlu
Keyword(s):  
Candida Albicans ◽  
Minimum Inhibitory Concentration ◽  
Amphotericin B ◽  
Combination Treatment ◽  
Liposomal Amphotericin ◽  
Inhibitory Concentration ◽  
Liposomal Amphotericin B ◽  
Control Group

The goal of this study was to compare in vitro and in vivo efficacy of moxifloxacin and liposomal amphotericin B (Amp-B) monotherapies and combination treatment against Candida albicans in an exogenous endophthalmitis model in rabbit eyes. Microplate dilution tests and checkerboard analysis were performed to detect in vitro efficacies. Endophthalmitis was induced by intravitreal injection of C. albicans in 40 rabbit eyes with simultaneous intravitreal drug injection according to prophylactic treatment groups. Group 1 (control group) received 0.1 mL of balanced salt solution, group 2 (moxi group) 100 µg moxifloxacin/0.1 mL, group 3 (Amp-B group) 10 µg liposomal Amp-B/0.1 mL, and group 4 (combi group) both 100 µg moxifloxacin/0.05 mL and 10 µg liposomal Amp-B/0.05 mL intravitreally. Clinical examination, quantitative analysis of microorganisms, and histopathologic examination were performed as in vivo studies. The minimum inhibitory concentration of liposomal Amp-B against C. albicans was found to be 1 µg/mL. Moxifloxacin showed no inhibition of in vitro C. albicans growth. The minimum inhibitory concentration values of liposomal Amp-B for C. albicans were reduced two- to eightfold with increasing concentrations of moxifloxacin in vitro. In vivo, there was no C. albicans growth in the combi group (zero of eight eyes), whereas three eyes (37.5%) showed growth in the Amp-B group. Vitreous inflammation, retinal detachment, focal retinal necrosis, and outer nuclear layer loss were found to be lower in the moxi group compared with the control group. Ganglion cell and inner nuclear layer loss was observed in all eyes (100%) in both the moxi and combi groups, whereas only in 25% (two of eight eyes) in the Amp-B group. Moxifloxacin strongly augments the efficacy of liposomal Amp-B against C. albicans in vitro, although it has no in vitro antifungal activity when used alone. It is interesting that we found a synergistic effect for in vitro tests but failed to demonstrate it in vivo. When 100 µg moxifloxacin/0.1 mL is given intravitreally, it has some toxic effects that are limited to the inner retinal layers.

scholarly journals In Vitro and In Vivo Exposure-Effect Relationship of Liposomal Amphotericin B against Aspergillus fumigatus

2019 ◽  
Vol 63 (6) ◽  
Author(s):  
Maria Siopi ◽  
Johan W. Mouton ◽  
Spyros Pournaras ◽  
Joseph Meletiadis
Keyword(s):  
Aspergillus Fumigatus ◽  
Amphotericin B ◽  
Liposomal Amphotericin ◽  
Simulation Analysis ◽  
Maximal Activity ◽  
Liposomal Amphotericin B ◽  
Content Type ◽  
Exposure Effect

ABSTRACT In vitro pharmacokinetic/pharmacodynamic data of liposomal amphotericin B (L-AMB) were compared with animal data from neutropenic and nonneutropenic models of azole-susceptible and azole-resistant invasive aspergillosis. L-AMB was equally effective. The in vitro fCmax (maximum concentration of free drug)/MIC ratio associated with 50% of maximal activity was 0.31 (0.29 to 0.33), similar to that in neutropenic but not nonneutropenic mice (0.11 [0.06 to 0.20]). Simulation analysis indicated that standard L-AMB doses (1 to 3 mg/kg) are adequate for nonneutropenic patients, but higher doses (7.5 to 10 mg/kg) may be required for neutropenic patients for Aspergillus fumigatus isolates with MICs of 0.5 to 1 mg/liter.

scholarly journals In vitro activities of amphotericin B deoxycholate and liposomal amphotericin B against 604 clinical yeast isolates

2014 ◽  
Vol 63 (12) ◽  
pp. 1638-1643 ◽  
Author(s):  
Maria Teresa Montagna ◽  
Grazia Lovero ◽  
Caterina Coretti ◽  
Osvalda De Giglio ◽  
Domenico Martinelli ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Liposomal Amphotericin ◽  
Liposomal Amphotericin B ◽  
Issatchenkia Orientalis ◽  
Highly Active ◽  
Wide Range ◽  
Amphotericin B Deoxycholate ◽  
Invasive Infections ◽  
A3 Method

We determined the in vitro antifungal activity of liposomal amphotericin B (L-AmB) against 604 clinical yeast isolates. Amphotericin B deoxycholate (D-AmB) was tested in parallel against all the isolates. Susceptibility testing was performed according to the Clinical and Laboratory Standards Institute (CLSI) M27-A3 method. Overall, L-AmB was highly active against the isolates (mean MIC, 0.42 µg ml−1; MIC90, 1 µg ml−1; 97.2 % of MICs were ≤1 µg ml−1) and comparable to D-AmB (mean MIC, 0.48 µg ml−1; MIC90, 1 µg ml−1; 97.3 % of MICs were ≤1 µg ml−1). The in vitro activity of D-AmB and L-AmB was correlated (R 2 = 0.61; exp(b), 2.3; 95 % CI, 2.19–2.44, P<0.001). Candida albicans (mean MICs of D-AmB and L-AmB, 0.39 µg ml−1 and 0.31 µg ml−1, respectively) and Candida parapsilosis (mean MICs of D-AmB and L-AmB, 0.38 µg ml−1 and 0.35 µg ml−1, respectively) were the species most susceptible to the agents tested, while Candida krusei (currently named Issatchenkia orientalis) (mean MICs of D-AmB and L-AmB, 1.27 µg ml−1 and 1.13 µg ml−1, respectively) was the least susceptible. The excellent in vitro activity of L-AmB may have important implications for empirical treatment approaches and support its role in treatment of a wide range of invasive infections due to yeasts.

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